Timothy P. Cooley

Low-dose compared with standard-dose m-BACOD chemotherapy for non-Hodgkin's lymphoma associated with human immunodeficiency virus infection

BACKGROUND Reduced doses of cytotoxic chemotherapy or standard-dose therapy plus a myeloid colony-stimulating factor decreases hematologic toxicity and its complications in patients with non-Hodgkins lymphoma associated with infection with the human immunodeficiency virus (HIV). However, the effect of reducing the doses of cytotoxic chemotherapeutic agents on clinical outcome is not known. METHODS We randomly assigned 198 HIV-seropositive patients with previously untreated, aggressive non-Hodgkins lymphoma to receive standard-dose therapy with methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone (m-BACOD) along with granulocyte-macrophage colony-stimulating factor (GM-CSF; n=94) or reduced-dose m-BACOD with GM-CSF administered only as indicated (n=98). RESULTS A complete response was achieved in 39 of the 94 assessable patients assigned to low-dose therapy (41 percent) and in 42 of the 81 assessable patients assigned to standard-dose therapy (52 percent, P= 0.56). There were no significant differences in overall or disease-free survival; median survival times were 35 weeks for patients receiving low-dose therapy and 31 weeks for those receiving standard-dose therapy (risk ratio for death in the standard-dose group=1.17; 95 percent confidence interval, 0.84 to 1.63; P=0.25). Toxic effects of chemotherapy rated grade 3 or higher occurred in 66 of 94 patients assigned to standard-dose therapy (70 percent) and 50 of 98 patients assigned to low-dose treatment (51 percent, P=0.008). Hematologic toxicity accounted for the difference. CONCLUSIONS As compared with treatment with standard doses of cytotoxic chemotherapy (m-BACOD), reduced doses caused significantly fewer hematologic toxic effects yet had similar efficacy in patients with HIV-related lymphoma. Dose-modified chemotherapy should be considered for most HIV-infected patients with lymphoma.

Fumagillin analog in the treatment of Kaposi's sarcoma: a phase I AIDS Clinical Trial Group study. AIDS Clinical Trial Group No. 215 Team.

PURPOSE Angiogenesis is a major component of Kaposis sarcoma (KS) and a critical process in tumor growth. The present study was designed primarily to test the toxicity and pharmacokinetics (PK) of the angiogenesis inhibitor TNP-470 and secondarily to evaluate tumor response in patients with early AIDS-related KS. PATIENTS AND METHODS Patients with AIDS-related KS were required to have cutaneous disease with > or = 5 measurable lesions and no evidence of pulmonary, symptomatic gastrointestinal, or acutely life-threatening KS. Thirty-eight patients received TNP-470 by weekly intravenous infusion over 1 hour at one of six dose levels for up to 24 weeks. RESULTS The dose levels tested included 10, 20, 30, 40, 50 and 70 mg/m2. Median CD4 count was 24 cells/microl (range, 0 to 460). Fourteen patients (36%) had > or = 50 cutaneous lesions and 19 (49%) had oral lesions. Adverse events included neutropenia (n = 2), hemorrhage (n = 3), and urticaria (n = 1). PK studies showed wide interpatient and intrapatient variability. Elimination half-life values were short (range, 0.01 to 0.61 hours). Seven patients (18%) achieved a partial response. The median time to partial response was 4 weeks (range, 2 to 25), and the median duration of response was 11 weeks (range, 3 to 26+). CONCLUSION TNP-470, administered as a weekly, 1-hour infusion to patients with early AIDS-KS is well-tolerated at doses up to and including the highest dose tested. Tumor responses were observed in a substantial number of cases and occurred at various dose levels. TNP-470 should be evaluated further in patients with AIDS-KS as a single agent and in combination with other biologic response modifiers in early disease or after initial response to cytotoxic chemotherapy.

Development of HIV-1 resistance to (-)2'-deoxy-3'-thiacytidine in patients with AIDS or advanced AIDS-related complex

Objective: To determine the rate of development of in vitro HIV resistance to (‐)2′‐deoxy‐3′‐thiacytidine (3TC) and relate the effect of dose to emergence of resistance. Methods: HIV‐infected men and non‐pregnant women, aged ≥ 18 years, with a CD4 count ≤ 300 × 106/l cells were fòllowed in a Phase I/II study, in which they were evaluated for tolerance to 3TC and effect of this agent with regard to viral susceptibility. Peripheral blood and plasma samples were collected at regular intervals for analysis. HIV was isolated using umbilical cord blood mononuclear cells as targets. These cells were also used in determinations of median inhibitory drug concentration. Specific amplification of the 184 mutation site, associated with HIV resistance to 3TC, was performed by polymerase chain reaction, using specific primer pairs, on DNA harvested from infected peripheral blood mononuclear cells (PBMC) of donors or, alternatively, on DNA that had been reverse transcribed from plasma‐associated HIV RNA. Results: Phenotypic resistance was detected in approximately one‐third of individuals studied, who were followed between 8 and 56 weeks. Development of 3TC resistance occurred independently of dose, although time of first appearance of resistant HIV‐1 variants appeared reduced at high 3TC doses. Amino‐acid changes at codon 184 in HIV‐1 reverse transcriptase were associated with, and preceded, the development of phenotypic 3TC resistance. Most commonly, a Met to Ile substitution appeared transiently before being superceded by a Val substitution at codon 184. Conclusions: In vitro resistance to 3TC developed in a high proportion of subjects who received prolonged monotherapy with this drug. The development of resistance to 3TC was associated with appearance of mutated viral forms and the disappearance of wild‐type virus, with regard to codon 184, in both patient plasma and PBMC. AIDS 1995, 9:351‐357

A comparison of stavudine plus lamivudine versus zidovudine plus lamivudine in combination with indinavir in antiretroviral naive individuals with HIV infection : selection of thymidine analog regimen therapy (START I)

BackgroundNo clinical trial results directly comparing two nucleoside analog pairs in a drug regimen for HIV that includes a protease inhibitor are available. ObjectiveTo compare the safety and efficacy of stavudine (d4T) + lamivudine (3TC) with zidovudine (ZDV) + 3TC, each in combination with indinavir (IDV). DesignRandomized, open-label, multi-center. SettingFifteen HIV clinical research centers. PatientsTwo-hundred and four antiretroviral-naive HIV-1-infected-patients with CD4 cell counts ⩾ 200 × 106/l and HIV-1 RNA ⩾ 10 000 copies/ml (bDNA assay), modified to 5000 copies/ml. Interventiond4T 40 mg twice a day, 3TC 150 mg twice a day plus IDV 800 mg every 8 h compared with ZDV 200 mg every 8 h (modified to 300 mg every 12 h) plus 3TC and IDV. MeasurementsPrimary endpoint: plasma HIV-1 RNA < 500 copies/ml. Additional endpoints: HIV-1 RNA ⩽ 50 copies/ml; change from baseline in HIV-1 RNA and CD4 cell counts; safety and adverse events. ResultsFor HIV-1 RNA, 62% of patients on d4T + 3TC + IDV and 54% of patients on ZDV + 3TC + IDV had < 500 copies/ml HIV RNA at weeks 40 through 48 [90% confidence interval, −0.204 to 0.036;P = 0.213], with 49% and 47% respectively achieving ⩽ 50 copies/ml at 48 weeks (90% CI, −0.134 to 0.096;P = 0.834). Median change in CD4 cell counts at 48 weeks was + 227 × 106/l and + 198 × 106/l for the d4T- and ZDV-containing arms, respectively. The median time-weighted average change from baseline in CD4 cell counts was significantly greater at 48 weeks in the d4T-containing arm (142 × 106/l versus 110 × 106/l;P = 0.033). Serious adverse events were not significantly different between treatment arms, but there were significant differences for frequency of adverse events of all severity with increased nausea and vomiting in the ZDV-containing arm, and increased diarrhea and rash in the d4T-containing arm. ConclusionsThese results support the choice of d4T + 3TC as a nucleoside analog pair in combination with a protease inhibitor in an initial HIV treatment regimen.

Antitumor activity of oral 9-cis-retinoic acid in HIV-associated Kaposi's sarcoma.

Objective To assess the efficacy, safety and tolerance of oral 9-cis- retinoic acid in HIV-infected patients with Kaposis sarcoma. Methods Sixty-six patients with AIDS-related Kaposis sarcoma were enrolled at 14 centers; 60 received the study medication and were analyzed and, of these, 45 (75%) had received prior therapy for Kaposis sarcoma. Once daily oral 9-cis-retinoic acid (alitretinoin, Panretin) was administered at doses up to 140 mg/m2. Most patients (72%) received a maximum dose of 100 mg/m2. Response was assessed using AIDS Clinical Trials Group (ACTG) criteria. Results The median age was 38 years and the median absolute CD4 cell count was 194 × 106 cells/l (range 6–784 × 106). Despite the use of three- and four-drug antiviral regimens (83%), the median HIV RNA at baseline was 8701 copies/ml [range < 500 (lower limit of detection) to 4.24 × 106]. The tumor response rate was 37% (95% confidence interval 25–49). Tumor response was associated with improved quality-of-life measures. There was a significant increase in interleukin 6 (IL-6) levels from baseline to week 4. Responders had significantly lower baseline soluble IL-6 receptor levels (P = 0.029) than non-responders. The median time to response was 9 weeks (mean, 13 weeks; range, 4–36). HIV RNA levels did not change significantly during therapy nor did they correlate with tumor responses. Study drug was discontinued by 28 patients for adverse events, which included headache (13) and skin toxicity (10). Conclusion Oral 9-cis-retinoic acid is an active antitumor drug for AIDS-related Kaposis sarcoma. Treatment is associated with skin and constitutional toxicity and further studies are needed to improve its long-term tolerance.

Highly Active Antiretroviral Therapy and Viral Response in HIV Type 2 Infection

Human immunodeficiency virus type 2 (HIV-2), the second human retrovirus known to cause AIDS, is endemic to West Africa but is infrequently found outside this region. We present a case series of 10 HIV-2--infected individuals treated in the United States. Physicians applied the principles of highly active antiretroviral therapy (HAART), normally used in treating HIV type 1, with modifications considered appropriate for treating HIV-2. CD4+ cell count, HIV-2 virus load, and clinical status were found to correlate well, providing evidence that HIV-2 virus load is useful in managing treatment of patients with HIV-2 who are receiving therapy. However, HAART regimens with predicted efficacy for treatment of HIV type 1 infection are not as efficacious for treatment of HIV-2. Controlled clinical trials of HIV-2-infected patients receiving various HAART regimens are needed to provide therapeutic guidance to the medical community.

Human Immunodeficiency Virus–Associated Primary Lung Cancer in the Era of Highly Active Antiretroviral Therapy: A Multi-Institutional Collaboration

BACKGROUND Human immunodeficiency virus (HIV)-infected individuals are at increased risk for primary lung cancer (LC). We wished to compare the clinicopathologic features and treatment outcome of HIV-LC patients with HIV-indeterminate LC patients. We also sought to compare behavioral characteristics and immunologic features of HIV-LC patients with HIV-positive patients without LC. PATIENTS AND METHODS A database of 75 HIV-positive patients with primary LC in the HAART era was established from an international collaboration. These cases were drawn from the archives of contributing physicians who subspecialize in HIV malignancies. Patient characteristics were compared with registry data from the Surveillance Epidemiology and End Results program (SEER; n = 169,091 participants) and with HIV-positive individuals without LC from the Adult and Adolescent Spectrum of HIV-related Diseases project (ASD; n = 36,569 participants). RESULTS The median age at HIV-related LC diagnosis was 50 years compared with 68 years for SEER participants (P < .001). HIV-LC patients, like their SEER counterparts, most frequently presented with stage IIIB/IV cancers (77% vs. 70%), usually with adenocarcinoma (46% vs. 47%) or squamous carcinoma (35% vs. 25%) histologies. HIV-LC patients and ASD participants had comparable median nadir CD4+ cell counts (138 cells/µL vs. 160 cells/µL). At LC diagnosis, their median CD4+ count was 340 cells/µL and 86% were receiving HAART. Sixty-three HIV-LC patients (84%) received cancer-specific treatments, but chemotherapy-associated toxicity was substantial. The median survival for both HIV-LC patients and SEER participants with stage IIIB/IV was 9 months. CONCLUSION Most HIV-positive patients were receiving HAART and had substantial improvement in CD4+ cell count at time of LC diagnosis. They were able to receive LC treatments; their tumor types and overall survival were similar to SEER LC participants. However, HIV-LC patients were diagnosed with LC at a younger age than their HIV-indeterminate counterparts. Future research should explore how screening, diagnostic and treatment strategies directed toward the general population may apply to HIV-positive patients at risk for LC.

FDG PET/CT in patients with HIV.

OBJECTIVE This article will discuss the (18)F-FDG normal variant uptake and the role of FDG PET/CT in malignancies in HIV-infected patients, CNS manifestations of HIV, assessing fever of unknown origin in HIV patients, assessing response to highly active antiretroviral therapy and assessing complications. CONCLUSION FDG PET/CT is a valuable imaging study in the management of HIV-infected patients.

Pegylated Liposomal Doxorubicin, Rituximab, Cyclophosphamide, Vincristine, and Prednisone in AIDS-Related Lymphoma: AIDS Malignancy Consortium Study 047

PURPOSE Infusional chemotherapy is efficacious in patients with AIDS-related lymphoma, but it may be difficult to administer. We studied standard agents with rituximab plus pegylated liposomal doxorubicin (DR-COP) in an attempt to provide a more practical approach to therapy while ascertaining rates of response, potential infectious complications, and prognostic role of biologic markers. PATIENTS AND METHODS We conducted a prospective, multi-institutional phase II trial, employing (day 1) pegylated liposomal doxorubicin 40 mg/m(2), rituximab 375 mg/m(2), cyclophosphamide 750 mg/m(2), vincristine 1.4 mg/m(2) (not > 2 mg), and prednisone 100 mg orally on days 1 through 5, with concomitant antiretroviral therapy. RESULTS In 40 evaluable patients, median CD4 cells was 114/μL (range, 5 to 1,026/μL), and median HIV-1 viral load (VL) was 25,000 copies/mL. High or intermediate/high age-adjusted International Prognostic Index was present in 28%. Overall response was 67.5%, with complete remission in 47.5% (95% CI, 31.5 to 63.9). Of 19 complete responders, 84% had extranodal disease, 47% had CD4 < 100/μL, and 47% had VL > 50,000 copies/mL; one relapsed. With 25.5-month median follow-up, 62% (95% CI, 44 to 75) of patients remain alive. Sixteen patients (40%) experienced 22 infections, with grade 4 in only two (5%). No patient died as a result of infection during treatment; one had opportunistic infection. CONCLUSION Profound immunodeficiency and high HIV-1 viral load do not preclude attainment of complete response after DR-COP with highly active antiretroviral therapy. The regimen is tolerable, and use of rituximab was not associated with death as a result of infection during treatment. This approach may be useful in patients in whom the more intensive infusional regimens are impractical.

Prognostic factors for advanced-stage human immunodeficiency virus-associated classical Hodgkin lymphoma treated with doxorubicin, bleomycin, vinblastine, and dacarbazine plus combined antiretroviral therapy: a multi-institutional retrospective study.

The treatment and outcomes of patients with human immunodeficiency virus (HIV)‐associated Hodgkin lymphoma (HL) continue to evolve. The International Prognostic Score (IPS) is used to predict the survival of patients with advanced‐stage HL, but it has not been validated in patients with HIV infection.